Assessing ECG signal quality indices to discriminate ECGs with artefacts from pathologically different arrhythmic ECGs.

False and non-actionable alarms in critical care can be reduced by developing algorithms which assess the trueness of an arrhythmia alarm from a bedside monitor. Computational approaches that automatically identify artefacts in ECG signals are an important branch of physiological signal processing which tries to address this issue. Signal quality indices (SQIs) derived considering differences between artefacts which occur in ECG signals and normal QRS morphology have the potential to discriminate pathologically different arrhythmic ECG segments as artefacts. Using ECG signals from the PhysioNet/Computing in Cardiology Challenge 2015 training set, we studied previously reported ECG SQIs in the scientific literature to differentiate ECG segments with artefacts from arrhythmic ECG segments. We found that the ability of SQIs to discriminate between ECG artefacts and arrhythmic ECG varies based on arrhythmia type since the pathology of each arrhythmic ECG waveform is different. Therefore, to reduce the risk of SQIs classifying arrhythmic events as noise it is important to validate and test SQIs with databases that include arrhythmias. Arrhythmia specific SQIs may also minimize the risk of misclassifying arrhythmic events as noise.

Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil.

Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-Tpeak) and late repolarization (global Tpeak-Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.

Improving the assessment of heart toxicity for all new drugs through translational regulatory science.

Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.

Butylmaduramycin, a new antibiotic from Actinomadura rubra.

Butylmaduramycin, a new derivative of maduramycin was isolated from the culture medium of a mutant strain of Actinomadura rubra. This communication describes some biological and physico-chemical characteristics of the new antibiotic.

On the mechanism of inhibitory effect of violamycin antibiotics on the transcription by bacteriophage T3-induced RNA polymerase.

The effect of three components of the anthracycline antibiotic violamycin on the transcription of bacteriophage T3 DNA by bacteriophage T3-induced RNA polymerase has been investigated in a cell-free system. The glycosides of violamycin BI possess the highest inhibitory activity, whereas those of violamycin BII and violamycin A show a reduced inhibitory effect. Concentrations of violamycin BI depressing the incorporation of (3H)UMP into RNA chains have only a slight effect on the binding of the T3 RNA polymerase to T3 DNA and on the incorporation of GTP as the first nucleotide. This shows that the primary target of the antibiotic is not the initiation of the RNA synthesis. The binding of violamycin BI to T3 DNA causes a strong reduction of the elongation rate of the RNA chains.

[Naphthoquinone antibiotics from Streptomyces lateritius. I Fermentation, isolation and characterization of granatomycins A, C, and D]. / Naphthochinon-Antibiotica aus Streptomyces lateritius I. Fermentation, Isolierung und Charakterisierung der Granatomycine A, C und D.

The fermentation and isolation procedures of the antibiotic granatomycin produced by Streptomyces lateritius are described. Furthermore, the producing strain ZIMET 43 627 and the main constituents of granatomycin will be characterized. Granatomycin is a red-violet pigment antibiotic of the naphthoquinone type. The physicochemical properties of granatomycin resemble those of granaticin. The antibiotic can be isolated from culture filtrates and from the mycelium by extraction with lower aliphatic alcohols. It can be purified by gel filtration methods. Granatomycin displays antimicrobial activity, particularly against grampositive and gramnegative bacteria, and antiviral activity against fowl-plaque-virus in mammalian cells. Granatomycin is useful in selection of resistant mutants of bacteria and viruses with decreased virulence but high immunogenity suitable for use as life vaccines against infection diseases. The physicochemical properties of the main constituents of granatomycin studied confirm the identity of granatomycin C with granaticin and the identity of granatomycin D with dihydrogranaticin Granatomycin A is identical with the well-known semisynthetic methylester of dihydrogranaticin. Therefore, the production of granatomycin A is the first possibility to produce this derivative of granaticin biosynthetically.

[Antineoplastic effects of violamycins depending on the number of sugar-components in the molecule (author's transl)]. / Zur antineoplastischen Wirkung der Violamycine in Abhängigkeit von den im Molekül enthaltenen Zuckern.

Violamycin B, an antibiotic-complex, inhibited the growth of Sarcoma 180 in a well defined manner. The products Violamycin A, BII, and BI obtained by gelfiltration, were tested against the lymphoid Leukemia L1210. The results showed an increase of the toxicity and, simultaneously, a decrease of the antineoplastic effect, depending on the number of the sugar-components.

[Antineoplastic activity of the anthracycline antibiotic violamycin BI in mice and rats using experimental metastases models (author's transl)]. / Antineoplastische Wirksamkeit des Anthracyclin-Antibiotikums Violamycin BI auf experimentelle Metastasen-Testmodelle bei Maus und Ratte.

The report describes the antineoplastic activity of violamycin BI on three rodent tumour systems. The test systems are two syngeneic mouse tumours: a benzo(a)pyrene induced sarcoma and a spontaneously originated mammary carcinoma of the inbred strain XVII/Berlin. Both tumours grow in ascitic form and were weekly passaged by i.p. administrations. A third system is a dimethylhydrazine induced rectum carcinoma of the Wistar rat. This rat tumour represents a slowly growing system transplanted by s.c. administrations of tumour fragments. The principle of the screening consists of the evaluation of metastatic parameters, e.g. weight, number and growth rate of metastases, experimentally induced by i.v. administrations of tumour cell suspensions. Under the given experimental conditions violamycin BI represents an antineoplastic antibiotikum with a good effectivity which is superior to the effectivity of the reference antibiotic daunorubicin.

Fermentation, isolation, and biological activity of maduramycin: a new antibiotic from Actinomadura rubra.

In a continuing search for new antibiotics, the species Actinomadura rubra (Sveshnikova et al.) J. Meyer et M. Sveshnikova 1974 (strain IMET 13001) was found to produce a red pigment with indicator properties, designated maduramycin. The pigment (C28H22O10; m.w. 518 m/e-; m.p. 305--310 degrees C (dec.); UVmax 225.307 nm) possesses a strong antimicrobial activity against gram-positive bacteria, including strains which produce inactivating enzymes for some commercial antibiotics. Maduramycin forms a complex with serum albumin, but no complex formation with DNA was observed using absorption spectroscopic and polarographic methods. Maduramycin additionally inhibits the action of some enzymes. The LC50 of maduramycin in mice was greater than 250 mg/kg on intraperitoneal administration. Fermentation, isolation, and some of the chemical and biological properties of this new antibiotic are described.

[Lambdamycin, an antibiotic from strain IMET 31118 of Streptomyces glaucoachromogenes Prauser. II. Physiochemical properties and comparison with chartreusin]. / Lambdamycin, ein Antibioticum aus dem Stamm IMET 31118 von Streptomyces glaucoachromogenes Prauser. II. Physikochemische Eigenschaften und Vergleich mit Chartreusin

The isolation and purification of the antibiotic lambdamycin are described. The physicochemical properties of the chromoglysoide lambdamycin resemble those of chartreusin. In this paper we compare the physicochemical properties of chartreusin and antibiotic X 465 with lambdamycin (alpha D, UV, IR). Lambdamycin is identified with chartreusin.